The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes

Lijun Sun, Li Deng, Chee Kwee Ea, Zong Ping Xia, Zhijian J. Chen

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Abstract

The CARD domain protein BCL10 and paracaspase MALT1 are essential for the activation of IκB kinase (IKK) and NF-κB in response to T cell receptor (TCR) stimulation. Here we present evidence that TRAF6 ubiquitin ligase and TAK1 protein kinase mediate IKK activation by BCL10 and MALT1. RNAi-mediated silencing of MALT1, TAK1, TRAF6, and TRAF2 suppressed TCR-dependent IKK activation and interleukin-2 production in T cells. Furthermore, we have reconstituted the pathway from BCL10 to IKK activation in vitro with purified proteins of MALT1, TRAF6, TAK1, and ubiquitination enzymes including Ubc13/Uev1A. We find that a small fraction of BCL10 and MALT1 proteins form high molecular weight oligomers. Strikingly, only these oligomeric forms of BCL10 and MALT1 can activate IKK in vitro. The MALT1 oligomers bind to TRAF6, induce TRAF6 oligomerization, and activate the ligase activity of TRAF6 to polyubiquitinate NEMO. These results reveal an oligomerization → ubiquitination → phosphorylation cascade that culminates in NF-κB activation in T lymphocytes.

Original languageEnglish (US)
Pages (from-to)289-301
Number of pages13
JournalMolecular Cell
Volume14
Issue number3
DOIs
StatePublished - May 7 2004

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TNF Receptor-Associated Factor 6
Ligases
Ubiquitin
Phosphotransferases
T-Lymphocytes
Ubiquitination
T-Cell Antigen Receptor
TNF Receptor-Associated Factor 2
Proteins
RNA Interference
Protein Kinases
Interleukin-2
Molecular Weight
Phosphorylation
Enzymes

ASJC Scopus subject areas

  • Molecular Biology

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The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. / Sun, Lijun; Deng, Li; Ea, Chee Kwee; Xia, Zong Ping; Chen, Zhijian J.

In: Molecular Cell, Vol. 14, No. 3, 07.05.2004, p. 289-301.

Research output: Contribution to journalArticle

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